Androgens are responsible for many physiological functions in both males and females. Androgen action is mediated by specific intracellular hormone receptors expressed in androgen responsive cells. Testosterone, the major circulating androgen, is secreted by Leydig cells of the testes under the stimulation of pituitary-derived luteinizing hormone (LH). However, reduction of the 4,5 double bond of testosterone to dihydrotestosterone (DHT) is required in some target tissues, such as prostate and skin, for androgen action. Steroid 5.alpha.-reductase in target tissues catalyzes conversion of testosterone to DHT in an NADPH dependent fashion as shown in Scheme A. ##STR4##
The requirement for DHT to act as an agonist in these target tissues has been highlighted by studies of steroid 5.alpha.-reductase deficient individuals who have vestigial prostate glands and do not suffer from acne vulgaris or male pattern baldness (see McGinley, The New England Journal of Medicine, 300, No. 22, p. 233-37, (1979)). Thus, inhibition of the conversion of testosterone to DHT in these target tissues is anticipated to be useful in the treatment of a variety of androgen responsive diseases, e.g., benign prostatic hypertrophy, prostate cancer, acne, male pattern baldness and hirsutism.
Because of their valuable therapeutic potential, testosterone 5.alpha.-reductase inhibitors [hereinafter "5.alpha.-reductase inhibitors"] have been the subject of active research worldwide. For example, see: Hsia, S. and Voight, W., J. Invest. Derm., 62, 224 (1973); Robaire, B., et al, J. Steroid Biochem., 8, 307 (1977); Petrow, V., et al., Steroids, 38, 121 (1981); Liang, T., et al., J. Steroid Biochem., 19, 385-390 (1983); Holt, D., J. Med. Chem., 33, 937 (1990); U.S. Pat. No. 4,377,584 and U.S. Pat. No. 5,017,568. Two particularly promising 5.alpha.-reductase inhibitors currently in clinical trials are MK-906 (Merck) and SKF-105657 (SmithKline Beecham), shown in Scheme B. ##STR5##